The significance of DNA damage and repair mechanisms in health risk assessment.
Clearly, the distinction of the three components in the underlying mechanisms of toxicity--pharmacokinetics, pharmacodynamics, and cell kinetics--is somewhat artificial. Together they form a continuous process rather than a set of stages. But these components correspond to the areas of studies that are often applied to the investigation of toxic mechanisms. Moreover, the components identify complexes of interacting processes, the consequences of which must be studied by examining their actions in concert with one another--metabolic activation must be examined as it competes with excretion, and rates of DNA-adduct formation must be studied along with mechanisms and rates of their repair. By enumerating these components, it becomes evident that clarification of the biological processes in only one realm, say pharmacokinetics, leaves other parts of the "black box" unrevealed. Components that are inadequately understood can be bridged either by plausible assumptions or by empirical measurement, but at the cost of some uncertainty in the risk extrapolations. For some processes, the artificial division into components may be problematic. For example, mutation rates clearly depend not only on the pharmacodynamic processes of creation of DNA adducts and their removal via repair, but also on the rates of cell division, allowing fixing of mutations, and on survival of the affected cells. The extrapolation of toxic effects across dose levels and across species hinges on the changes in the proportionality of input to output in each of the three components. Different degrees of metabolic activation of a procarcinogen across species clearly affect the comparative potency of an agent in experimental animals and human beings.(ABSTRACT TRUNCATED AT 250 WORDS)
Rhomberg
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Office of Health and Environmental Assessment, US Environmental Protection Agency, Washington, DC.
Dellarco
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Farland
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Cortesi
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D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage; D004260:DNA Repair; D005796:Genes; D006801:Humans; D009369:Neoplasms / Q000209:etiology*; D012307:Risk Factors